Chronic lung disease due to Mycobacterium avium complex, Mycobacterium chelonae, Mycobacterium abscessus, and Mycobacterium kansasii are an emerging and serious public health problem in the United States. The incidence of pulmonary disease caused by such NTM is increasing and recent reports suggest that in many areas of the U.S., the prevalence of NTM pulmonary disease exceeds that of tuberculosis. The cure rate for chronic lung infections due to NTM are low despite prolonged treatment with various multi-drug regimens. Little is known about the nature of the immunopathogenesis of NTM infections and how these organisms overcome host immunity and persist; this underlies the current lack of development of more efficacious and targeted therapies. The two limitations to developing new therapies for NTM, especially the particularly troublesome M. abscessus, are the lack of lead compounds for new drug development, and the lack of a validated animal model. Our recent preliminary data using infection of GKO-/- mice however showed that these mice still possessed robust innate immunity and were able to clear an infection with M. abscessus bacilli making this model unsuitable for drug screening. In this regard, we need to further understand the pathogenesis involved in bacterial clearance and persistence and evaluate new models in which the class of bacilli can actually grow to high levels so we can use these models to screen for new therapies. We propose in aim 1 to use GM-CSF-/-, MYD88-/-, TNFR-1-/-, C57BL/6NCrIBR and C3HeB/FeJ and mice to standardize a high aerosol and intravenous infection dose with characterized strains of M. avium complex, M. chelonae, M. abscessus, and M. kansasii to evaluate the subsequent pathogenesis and optimize the model for drug screening. In Aim 2 we propose to evaluate the efficacy of standard anti-NTM compounds against NTMs in these models.